1. Field of the Invention
This invention relates to 2-{[2-(substituted amino)ethyl]sulfonyl}ethyl N,N-bis(2-chloroethyl)-phosphorodiamidates and their salts, pharmaceutical compositions containing them, their pharmaceutical use, and their preparation and intermediates in their preparation.
2. Description of the Related Art
U.S. Pat. No. 5,556,942 [and PCT Publication No. WO 95/09865] discloses compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;Sx is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.The compounds are stated to be useful drugs for the selective treatment of target tissues which contain compatible glutathione S-transferase (GST) isoenzymes, and simultaneously elevate the levels of granulocyte macrophage progenitor cells in bone marrow. Disclosed embodiments for L include those that generate a drug that is cytotoxic to unwanted cells, including the phosphoramidate and phosphorodiamidate mustards.
PCT Publication No. WO 95/09865 also discloses intermediates that are compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;S+ is S or Se;S* is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.
U.S. Pat. No. 6,506,739 [and PCT Publication No. WO 01/83496] discloses compounds of the formula
where:X is a halogen atom;Q is O, S, or NH; andR is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is R′CO—, R′NHCO—, R′SO2—, or R′NHSO2— where R′ is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R-Q together is chlorine; and their salts,as antitumor agents.
US Patent Application Publication No. 2005/0267075 [and PCT Publication No. WO 2005/118601] discloses compounds of the formulae
where:each R is independently hydrogen, C1-6 alkyl, or —CH2CH2X, where each X is independently Cl, Br, C1-6 alkanesulfonyloxy, halo-C1-6 alkanesulfonyloxy, or benzenesulfonyloxy optionally substituted with up to three substituents selected from halo, C1-3 alkyl, halo-C1-3 alkyl, C1-3 alkyloxy, or halo-C1-3 alkyloxy, provided that at least two R's in each phosphorodiamidate group are —CH2CH2X;R1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; andR2 is optionally substituted alkanediyl, optionally substituted heteroalkanediyl, optionally substituted arenediyl, optionally substituted arenedialkyl, optionally substituted heteroarenediyl, or optionally substituted heteroarenedialkyl,and their salts,as antitumor agents.
Jain et al., “Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines”, J. Med. Chem., 47(15), 3843-3852 (2004), discloses a series of sulfonylethyl phosphorodiamidates of the formula
including compounds where R1═R2═CH2CH2Cl, R3═R4═H; R1═R3═CH2CH2Cl, R2═R4═H; and R1═R2═R3═R4═CH2CH2Cl. The compounds are said to spontaneously liberate phosphoramide mustards via beta-elimination, and to be more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro. Some of the compounds were said to show excellent in vivo antitumor activity in CD2F1 mice against the P388/0 (wild) and P388/CPA (cyclophosphamide-resistant) leukemia cell lines.
U.S. patent application Ser. No. 11/564,744 discloses compounds of the formula
and their salts,where each R is independently methyl, ethyl, propyl, or isopropyl, or —NR2 together is 1-pyrrolidinyl or 1-piperidinyl,as antitumor agents.
Cyclophosphamide is used for the treatment of a number of cancers (including lymphomas, multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and breast carcinoma) and, at lower doses, for the treatment of autoimmune diseases (including lupus, scleroderma, vasculitis, myopathies, and complications of rheumatoid arthritis). It is metabolically activated by enzymes in the liver to release acrolein and “cyclophosphamide mustard”, as follows:
and some of the toxicities of cyclophosphamide (in particular, cystitis) are attributed to the acrolein.
It would be desirable to develop chemically and pharmaceutically simple (easy to synthesize and formulate) compounds having an efficacy and safety as good as or better than cyclophosphamide.
The complete disclosures of the documents referred to in this application are incorporated into this application by reference.